Positive Anaplastic Large Cell Lymphoma Research Articles

An Isolated Cutaneous Relapse in a Known Case of Systemic ALK-Positive Anaplastic Large Cell Lymphoma: A Rare Case Report with Review of Literature

AbstractAmong non-Hodgkin's lymphomas (NHLs), anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a relatively uncommon subtype that accounts for 3% of all adult NHLs. It typically affects young males, with a prevalence of three to one. Most cases present with nodal disease at the time of presentation. An extranodal involvement is seen in 60% of cases and skin involvement is seen in only 8 to 21% of cases. Cutaneous involvement in ALCL can manifest as primary cutaneous ALCL or secondary to systemic ALCL, and while CD30 positivity is common to both, ALK is not expressed by the former. A secondary skin involvement is usually associated with a poorer prognosis.We report a rare case of an isolated cutaneous relapse of systemic ALK-positive ALCL in a 62-year-old woman following the second cycle of chemotherapy. The acute febrile, widespread papulonodular eruption clinically resembled mycosis fungoides and lymphomatoid papulosis. With the introduction of oral crizotinib, a drastic improvement in the skin lesions and an exceptional response on positron emission tomography-computed tomography were noted.

Overcoming Brigatinib Resistance with Lorlatinib in Pediatric ALK Positive Anaplastic Large Cell Lymphoma with Acquired ALK p.F1174V Mutation – a Case Report

Overcoming Brigatinib Resistance with Lorlatinib in Pediatric ALK Positive Anaplastic Large Cell Lymphoma with Acquired ALK p.F1174V Mutation – a Case Report

Treatment of primary cutaneous CD30‐positive anaplastic large cell lymphoma with Wenyang Shengji decoction and Huanglian ointment: A case report

AbstractPrimary cutaneous CD30 positive anaplastic large cell lymphoma (PC‐ALCL) is a rare non‐Hodgkin's lymphoma. Combined chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), MACOP‐B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), or F‐MACHOP (5‐fluorouracil, methotrexate, cytosine‐arabinoside, cyclophosphamide, doxorubicin, vincristine, and prednisone) are often used for its clinical treatment. In this study, we reported a new treatment method using a traditional Chinese therapy involving oral Wenyang Shengji decoction (WSD) combined with Huanglian ointment applied externally in a 32‐year‐old female patient with PC‐ALCL. Introduction: A 32‐year‐old woman who complained of an ulcer on the forehead accompanied by significant pain. PC‐ALCL was diagnosed by histopathological examination and immunohistochemical analysis. Treatment plan: WSD was prepared in 300 mL water and administered orally as a 150 mL decoction twice daily, and Huanglian ointment was applied to the ulcer three times daily. After 8 weeks of treatment with WSD combined with Huanglian ointment, the lesion healed completely. Immunohistochemical analysis revealed the presence of scattered CD3+++, CD4++, CD8++, CD20++, and CD30‐positive cells. After 12 weeks of treatment, the ulcer healed completely, leaving only a marked pale red‐pitted scar. The patient was followed up for 3 years without recurrence and no adverse events. Conclusion: oral WSD combined with Huanglian ointment applied to the ulcer for PC‐ALCL can promote the healing of ulcers, reduce or alleviate the formation of scar, and eliminate CD30‐positive cells. This case report provides a reference for the clinical treatment of PC‐ALCL using traditional Chinese medicine.

Cutaneous Lymphoma in a Tertiary Skin Hospital and Referral Centre in Nepal.

Primary cutaneous lymphomas are a distinct group of rare lymphoid neoplasms with absence of extracutaneous lymphomas at the time of presentation. They are rare in Nepal and no data on cutaneous lymphoma have been published from this country till date. This retrospective study included 15 cases of cutaneous lymphomas retrieved from the records of department of Dermatopathology, DI Skin Hospital and Referral Centre, Bansbari, Kathmandu, Nepal. Patients were diagnosed according to the current WHO classification for cutaneous lymphoma. A total of 15 cases were studied with median age of 45 years (range: 22 to 81 years) and male to female ratio of 1.5:1. Primary cutaneous lymphomas constituted 13 cases out of 15 and the most common type of cutaneous lymphoma was mycosis fungoides and variants 5 (33%), followed by CD30 positive primary cutaneous anaplastic large cell lymphoma constituting 2 (13%). T-cell cutaneous lymphoma constituted 13 (87%) and B-cell cutaneous lymphoma 2 (13%). Cutaneous T-cell lymphomas were more frequent than cutaneous B-cell lymphomas in Nepalese patients. Mycosis fungoides and variants are commonest type of primary cutaneous lymphomas.

Establishment and characterization of TK-ALCL1: a novel NPM-ALK-positive anaplastic large-cell lymphoma cell line.

TK-ALCL1, a novel anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) cell line, was established from the primary tumor site of a 59-year-old Japanese male patient. The immune profile of TK-ALCL1 corresponds to that seen typically in primary ALCL cells, i.e., positive for ALK, CD30, EMA, and CD4, but negative for CD2, CD3, CD5, CD8a, and EBV-related antigens. The rearrangement of the T cell receptor-gamma locus shows that TK-ALCL1 is clonally derived from T-lineage lymphoid cells. FISH and RT-PCR analysis revealed that TK-ALCL1 has the nucleophosmin (NPM)-ALK fusion transcript, which is typical for ALK+ ALCL cell lines. When TK-ALCL1 was subcutaneously inoculated into 6-week-old BALB/c Rag2-/-/Jak3-/- (BRJ) mice, it formed tumor masses within 4-6weeks. Morphological, immunohistochemical, and molecular genetic investigations confirmed that the xenograft and the original ALCL tumor were identical. The ALK inhibitors Alectinib and Lorlatinib suppressed proliferation in a dose-dependent manner. Thus, TK-ALCL1 provides a useful in vitro and in vivo model for investigation of the biology of ALK+ ALCL and of novel therapeutic approaches targeting ALK.

Variant ALK-fusion positive anaplastic large cell lymphoma (ALCL): A population-based paediatric study of the NHL-BFM study group.

Frequency, distribution and prognostic meaning of ALK-partner genes other than NPM1 in ALK-positive anaplastic large-cell lymphoma (ALCL) are unknown. Forty-nine of 316 ALCL diagnosed in the NHL-BFM study group showed no nuclear ALK expression suggestive of a variant ALK-partner; 41 were analysed by genomic capture high-throughput sequencing or specific RT-PCRs. NPM1::ALK was detected in 13 cases. Among the 28 patients with a non-NPM1::ALK-fusion partner, ATIC (n = 8; 29%) and TPM3 (n = 9; 32%) were the most common. Five of eight patients with ATIC::ALK-positive ALCL relapsed, none of nine with TPM3::ALK. Variant ALK-partners are rare and potentially associated with different prognoses.

A Rare Case of Primary Bone Lymphoma Masquerading as Langerhans Cell Histiocytosis

Anaplastic Large Cell Lymphoma (ALCL) is an uncommon type of Non Hodgkin Lymphoma (NHL). It commonly arises in lymph nodes and can also involve extranodal sites such as the skin, soft tissues, lungs, bones, and liver. Here, a case of Anaplastic Lymphoma Kinase (ALK)-positive ALCL in a 17-year-old male patient who presented with swelling in the frontal and occipital bones is presented. The patient was clinically and radiologically diagnosed with Langerhans Cell Histiocytosis (LCH), and excision of the occipital lesion was performed. Preoperatively, lymphoma was not considered a differential diagnosis. Detailed histopathological examination, immunohistochemistry, and Positron Emission Tomography (PET) scan confirmed the diagnosis of primary bone ALK-positive ALCL. This T-cell NHL is composed of large lymphoid cells with abundant cytoplasm and pleomorphic horseshoe or kidney-shaped nuclei, with characteristic ALK and CD30 positivity. An isolated presentation of ALCL as a primary lesion in the bone is extremely rare. Clinicians and pathologists should be aware of this rare presentation, as prompt diagnosis and proper treatment can lead to favourable outcomes.

A rare cause of intestinal obstruction: jejunal ALK positive anaplastic large-cell lymphoma.

A 32-year-old man had recurrent abdominal pain and vomiting for 2 weeks. Physical examination revealed a 4×2-cm abdominal tough mass with unclear boundaries. Palpation caused mild tenderness without rebound pain. Computed tomography (CT) showed a proximal jejunal mass with incomplete small-bowel obstruction , and double-balloon enteroscopy showed a large protruding proximal jejunal mass covered with dirt and a narrow lumen ; an enteroscope would not pass through. Pathological diagnosis by insufficiently deep endoscopic biopsy is difficult. After multidisciplinary discussion, surgical resection was performed. Histopathology revealed a malignant tumor . Immunohistochemical results: CD30 (+), ALK (+), EMA (+), GrB (+), CD2 (+), CD43 (+), TIA-1 (+), and silver staining (+). Sarcoma 86 fusion-gene detection showed NPM1-ALK gene rearrangement. The patient was diagnosed with anaplastic large-cell lymphoma (ALCL) and underwent chemotherapy.

Strategy for Pediatric Patients with Relapsed or Refractory Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma: A Review.

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL. These include morphological patterns with the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL is often resistant to conventional chemotherapy; therefore, salvage therapy is required. In recent years, targeted therapies such as ALK inhibitors and brentuximab vedotin (BV) have been developed. ALK inhibitors block the continuous activation of ALK kinase, a driver mutation that leads to cell proliferation in ALK-positive ALCL. Additionally, BV is an antibody-drug conjugate that targets CD30-positive cells. Both ALK inhibitors and BV have displayed dramatic effects in chemoresistant ALK-positive ALCL. Weekly vinblastine treatment and hematopoietic stem cell transplantation have also been reported to be effective therapies. This article reviews pediatric ALK-positive ALCL, focusing on risk factors and treatment strategies for pediatric patients with relapsed or refractory ALK-positive ALCL.

Prognostic Impact of Minimal Disseminated Disease (MDD) and Minimal Residual Disease (MRD) in Chinese Pediatric Patients with ALK-Positive Anaplastic Large Cell Lymphoma (ALCL)

# Keyan Yang and Jing Yang contribute equally to this article. * Corresponding to both Qinlong Zheng (zhengql@gobroadhealthcare.com) and Yonghong Zhang (zhangyongh@gobroadhealthcare.com) Backgrounds: Anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK+ALCL) is characterized by the occurrence of the ALK fusion and subsequently ALK fusion kinase protein expression. It has been reported that minimal disseminated disease (MDD) and minimal residual disease (MRD) detected by RQ-PCR are independent prognostic factors. Purpose & Methods: To explored the prognostic roles of MDD and MRD in Chinese pediatric patients with ALCL, we conduct a retrospective study in a cohort of 204 Chinese children and adolescent ALK+ALCL patients treated at multiple centers of the China Network of Childhood Lymphoma (CNCL). The median follow-up time was 39 months (95%CI: 34-44.7). MDD level as ALK fusion copy number was measured by quantitative RT-PCR at the initial diagnosis. Based on the Overall Survival (OS) data, cut-off values of 1.63 in peripheral blood (PB) and 1.43 in bone marrow (BM) were determined by using the maximally selected rank statistics, with the c-index values of 0.904 in PB and 0.895 in BM. Results: The prevalence of MDD in PB and/or BM of Chinese pediatric patients with ALK+ALCL was 24.8%, while the MDD level were significantly correlated between PB and BM (R=0.8, p<2.2e-16). In addition, the 3-year OS (PB, 87.8% vs. 100%; BM, 87.9% vs. 100%) and EFS (PB, 73.2% vs. 94.8%; BM, 80.0% vs. 93.2%) were revealed with significant difference, when analyzed by MDD level. The combined analyses of both MDD level (with the same cut-off value) and MRD results (positive vs. negative), either after 1 st course of treatment (MRD1) or 2 nd course of treatment (MRD2), indicated the further poor prognosis, both in 3-year OS (PB, MRD1, 64.8% vs. 100%, MRD2, 72.9% vs. 100%; BM, MRD1, 64.8% vs. 100%, MRD2, 68.8% vs. 100%) and EFS (PB, MRD1, 40.0% vs. 95.3%, MRD2, 45.0% vs. 95.1%; BM, MRD1, 40.0% vs. 94.7%, MRD2, 35.7% vs. 94.4%). Conclusion: Summary, in this work, MDD level detected by quantitative RT-PCR was revealed as a strong factor in prognostic evaluation of Chinese children and adolescent patients with ALK+ALCL, which showed its important role in clinical detection at initial diagnostic. In future, the further validation work could be carried out in different cohort of ALK+ALCL patients, even with larger enrolled population size and longer follow-up time.

Distinct Subtypes of Chemotherapy-Resistant Systemic ALK-Positive Anaplastic Large Cell Lymphoma Demonstrate Long-Term Complete Remissions to Imatinib

Background Platelet-derived growth factor receptor (PDGFR) is expressed in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) positive anaplastic large cell lymphomas (ALCL ALK+). Our previous preclinical research suggested that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib could be an effective treatment strategy for ALCL ALK+. An indicator patient whose ALCL cells expressed PDGFR and who failed three treatment lines (including autologous stem cell transplantation) achieved complete remission (CR) with imatinib. Methods We treated 6 relapsed/refractory (r/r) ALK+ ALCL patients with imatinib, 4 of which within the prospective clinical trial, EudraCT No.: 2013-003505-26. Median follow-up was 40 months (160 weeks, range 4 - 428). Patients were characterized by whole exome sequencing, bisulfite sequencing, RNA-sequencing and immunological profiling. Whole exome sequencing data were integrated and compared to 32 additional ALK+ ALCL patients (Larose et. al., Haematologica, 2021; Creszenzo et al., Cancer Cell 2015; Mologni et al. (unpublished). Results 5-year progression-free survival (PFS) was 67%. 4 out of 6 patients achieved a CR that was maintained throughout the follow-up of 3.3 - 8.9 years. Lymphoma cells of the non-responding patients did not express PDGFRA/B as confirmed by immunohistochemistry and RNA-scope (panel figure A). Cytoplasmic co-expression of both, ALK and PDGFRA/B, in ALCL tumor cells was associated with complete response to imatinib in ALK+ ALCL patients. Methylation profiling confirmed a differentially activated PDGFR axis between responders and non-responders and identified a specific protein kinase profile that included a significant inflammatory upregulation of HGFAC, VEGFa, and TNFa in serum cytokine profiling. The transcriptional differential gene expression includes an upregulation of genes of GO:0045859 (regulation of protein kinase activity) in non-resonders. Ident pathologic variants resulting in amino-acid changes were detected in non-responders in mutated genes linked to kinase activity ( TBC1D28 E56A), protein processing ( EMC1 S323T: cosmicV64345386 and EMC1S325N: cosmicV100916421; and GOLGA8S) and cytokine signaling ( IFNL2, ZFYVE19). The imatinib-resitance profile involving mutations in EMC1 and GOLGA8S could be detected at a frequency of 6/32 (19%) in an independent reference cohort of r/r ALK+ALCL (panel figure B). Exclusive mutations in PPP1R13B linked to p53-pathway were found in all responders. PDGFRA mutations with low allele frequencies (2-5%) were identified soley in imatinib-responders. Additionally, non-responders were characterized by an exclusive mutational signature linked to vesicular endocytosis and cytokine signaling as a resistance mechanism to pan-kinase inhibitor imatinib. Conclusion PDGFRA/B expression in tumour cells of therapy-resistant ALK-positive ALCL patients can discriminate genetically and functionally distinct lymphoma subgroups that are directly related to long-term treatment response to kinase inhibitor imatinib. Our data suggests that significant imatinib responses may be achieved in more than 80% of chemotherapy-resistant ALK+ ALCL cases.

MiR-146a-5p enrichment in small-extracellular vesicles of relapsed pediatric ALCL patients promotes macrophages infiltration and differentiation

Anaplastic large cell lymphoma (ALCL) is a CD30-positive lymphoma accounting for 20% of all pediatric T-cell lymphomas. Current first line treatment can cure most of ALCL patients but 10-30% of them are resistant or relapse. In this context, liquid biopsy has the potential to help clinicians in disease screening and treatment response monitoring. Small-RNA-sequencing analysis performed on plasma small-extracellular vesicles (s-EVs) from 20 pediatric anaplastic lymphoma kinase positive (ALK+) ALCL patients at diagnosis revealed a specific miRNAs cargo in relapsed patients compared to non-relapsed, with seven miRNAs enriched in s-EVs of relapsed patients. MiR-146a-5p and miR-378a-3p showed a negative prognostic impact both in univariate and multivariate analysis, possibly representing, together with let-7g-5p, a miRNA panel for the early identification of high-risk patients. Among them, miR-146a-5p is known to modulate tumor supporting-M2 macrophages differentiation, but the role of these cells in pediatric ALK+ALCL is still unknown. To elucidate the role of miR-146a-5p and M2 macrophages in pediatric ALCL disease, THP-1-derived macrophages were treated with s-EVs from ALK+ALCL cell lines, showing increased miR-146a-5p intracellular expression, migrating capability and M2-markers CD163 and Arginase-1 upregulation. In turn, conditioned media from M2 macrophages or miR-146a-5p-transfected THP-1 increased ALCL cells' aggressive features and were enriched in interleukin-8. Overall, these data suggest a role of miR-146a-5p in promoting macrophage infiltration and M2-like polarization in ALCL. Our findings incite further investigation on the role of M2 macrophages in ALCL aggressiveness and dissemination, also considering the novel treatment options targeting tumor associated macrophages.

Anaplastic Large-cell Lymphoma Involving Gastrointestinal Tract: A Clinicopathologic Study of 25 Cases of a Rare Tumor at a Rare Site.

Background. Anaplastic large-cell lymphoma (ALCL) is an uncommon lymphoma divided into anaplastic lymphoma kinase (ALK) positive, ALK negative, and breast implant-associated (BIA) ALCL. Gastrointestinal tract involvement is very rare and may be difficult to diagnose. Its recognition is crucial as prognostic ramifications are different. Objectives. To describe clinicopathological features of ALCL involving the gastrointestinal tract. Materials and Methods. Slides were reviewed. Diagnosis was confirmed. Histological and immunohistochemical features were described. Results.Twenty-five tumors were diagnosed during the study period. Ages ranged from 14 to 65 years (mean 41 years). Mean age for ALK-negative and ALK-positive patients were 49 and 17 years, respectively. Twenty-one were males and 4 were females. Eighteen involved small intestine. Mean tumor size was 4.2 cm. All showed diffuse sheets of large anaplastic cells with pleomorphic nuclei, abundant pink cytoplasm, and strong positivity for CD30. Epithelial membrane antigen was positive in 17 tumors and keratin was negative in all. Eighteen tumors were ALK negative. Out of 14 patients with follow-up, 12 died within a few months of diagnosis. Seven had stage IE, 5 had stage IIE, and 2 had stage IV disease. Two patients were alive at 35 and 60 months. Twelve received chemotherapy. Conclusion. A marked male predominance was noted. Small intestine was the commonest site of involvement. Majority were ALK negative. ALK-negative tumors occurred in older patients and ALK positive in younger patients. Prognosis was poor. ALCL should be included in the differential diagnosis of anaplastic epithelioid cell neoplasms in the gastrointestinal tract.

Observation of Alectinib- and Crizotinib- included chemotherapy in children with ALK-positive anaplastic large cell lymphoma: A single institutional experience.

Approximately one-third children with anaplastic large cell lymphoma (ALCL) relapse after completion of chemotherapy, particularly for those high-risk patients. The introduction of novel therapeutic modalities is much needed for these sub-group patients. Two groups (n= 3, n= 4) of ALCL patients were treated with crizotinib- and alectinib-included ALCL-99 therapy, respectively, achieving complete remission rates of 66.7% and 100%. Two patients of crizotinib group relapsed, while none relapsed among the alectinib-treated patients. Adding alectinib instead of crizotinib sufficiently suppressed and maintained the deep NPM-ALK molecular response. ALK inhibitors were well tolerated with only grade 1 adverse events in both groups. Though a relatively small case number, this study raised the possibility that alectinib-included therapeutic regimens may benefit the early response, in-depth molecular remission, and persistent remission to some extent. Further studies are warranted to validate our preliminary findings.

Phase I Study of Tq-B3101 in Pediatric Patients with Relapsed/Refractory Anaplastic Lymphoma Kinase Positive Anaplastic Large Cell Lymphoma

Background Anaplastic large cell lymphoma (ALCL) accounts for 10-30% of childhood lymphomas, and 90% of pediatric and adolescent patients (pts) are Anaplastic Lymphoma Kinase positive ALCL (ALK+ ALCL). The results of ADVL0912 (NCT00939770) and A8081013 (NCT01121588) studies suggest that the ALK inhibitor crizotinib has good efficacy and safety in the treatment of ALK+ALCL. The recommended pediatric dose of crizotinib is 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. TQ-B3101 is a novel kinase inhibitor for ROS1, ALK, and c-MET kinases. After oral administration, TQ-B3101 undergoes deacetylation to form crizotinib. In animal models, TQ-B3101 significantly inhibited the phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2) in ALK downstream signaling pathway in tumor tissue, with a longer inhibition time and stronger inhibition compared to equimolar crizotinib. This study aimed to explore the safety and efficacy of TQ-B3101 in pediatric patients with ALK+ ALCL. Methods TQ-B3101-II-02 is an open-label, single-arm, phase I dose escalation and pharmacokinetic study. Eligible pts were 10 to 18 years of age with relapsed/refractory (R/R) ALK+ALCL. We used a 3+3 design to determine the maximum tolerated dose (MTD). The dose levels to be investigated were 200mg BID, 250mg BID, and 300mg BID. Dose-limiting toxicities (DLT) were defined in cycle one (28-day) as any grade 4 hematologic toxicity or any grade 3 non-hematologic toxicity, except for alopecia and electrolyte disturbances that resolved within 3 days. The primary endpoints were safety and pharmacokinetics (PK). Secondary endpoints included overall response rate (ORR), progression free survival (PFS), and overall survival (OS). Responses were evaluated by investigators per the 2014 Lugano classification based on positron emission tomography/computed tomography (PET/CT) scans. This trial was registered at www.clinicaltrials.gov as # NCT04306887. Results All seven patients enrolled were evaluable for toxicities and response, with four males/three females, a median age of 12 years (range, 10-14 years), a median weight of 40.0 kg (range, 32.9-68.0 kg), a median height of 152.0 cm (range, 143.5-169.5 cm), and a median body surface area (BSA) 1.27 m2 (range, 1.15-1.73 m2). Three patients, three patients, and one patient with ALCL were treated at doses of 200mg, 250mg, and 300mg, respectively. The majority of patients (57.1%) had a median Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 1. Two patients had a refractory disease and five had relapsed disease. Histological diagnosis of ALK-positive ALCL was confirmed by immunohistochemistry. The area under the curve (AUC)(0-t) of the three dose groups after the first administration were 492 ± 285, 606 ± 288, and 914 μg/L*h, respectively, and the AUC(0-t) after the last administration was 2311 ± 997, 3749 ± 407, 3311 μg/L*h. The in vivo exposure of deacetylated metabolites generated after a single dose was lower than that of crizotinib, and after 28 days of continuous dosing, the in vivo exposure was similar to that of crizotinib (BSA-adjusted dose). The most frequently reported treatment-related adverse events (TRAEs) were hypothyroidism (n = 6), vomit (n = 6), reduced neutrophil count (n = 6). Four pts (57.1%) had grade 3-4 TRAEs. No treatment-related death and DLTs were observed. The ORR was 100%, with four patients achieving complete response (CR) and three patients achieving a partial response (PR). The median time to respond was 1.9 months (range 1.8, 2.0). Six pts had a ≥ 60% tumor reduction. As of the cut-off date of July 22, 2022, the four pts with CR received TQ-B3101 beyond 20 cycles (range, 20-34 cycles) and remained progression-free at 18.7 to 27.9 months. The three pts with PR progressed after 3 to 4 cycles of treatment and discontinued TQ-B3101. One patient voluntarily withdrew from the study. All seven patients were still alive, with the longest survival time of more than 32 months. Conclusion Our preliminary results suggest that TQ-B3101 has significant clinical activity in children with R/R ALK+ ALCL. Responses were durable and ongoing, and treatment was well tolerated. Further investigation is warranted to find the MTD and confirm the efficacy of TQ-B3101. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Follow-up of Clinical Outcome Determinants and Correlative Biological Features from the Nordic NLG-T-01 Trial

Introduction The Nordic NLG-T-01 was a large phase II trial evaluating the efficacy of bi-weekly etoposide-containing chemotherapy consolidated by autologous transplant in newly diagnosed patients with systemic peripheral T-cell lymphomas (PTCL) (d'Amore et al, JCO 2012). The final analysis of the trial showed female sex and anaplastic large cell (ALCL) histology to be predictive of a favourable outcome. Here, we present a long-term follow-up evaluating the outcome of NLG-T-01 patients according to clinico-pathological parameters and biological features, in particular rearrangements of the dual specificity phosphatase 22 (DUSP22-IRF4) and the TP63 gene. Methods A cohort of 160 adult PTCL patients aged 18 to 67 years were enrolled. Anaplastic lymphoma kinase (alk)-positive anaplastic large-cell lymphoma (ALCL), primary cutaneous and primary leukemic PTCL were excluded. Considering the high median age of the study population at the time of enrolment (57 yrs) and the length of follow-up, we analyzed, in addition to overall (OS) and progression-free survival (PFS), also disease-specific survival (DSS). Time-to-event end points were calculated by means of Kaplan-Meier estimates. Log-rank tests and Cox regression models were used to analyze prognostic factors. A trial-specific tissue micro-array (TMA) was constructed with those pre-therapeutic biopsies, where sufficient tissue was still available for analysis (n=87). Fluorescent in situ hybridization (FISH) was performed on TMA slides or whole sections using break apart probes for the DUSP22-IRF4 and TP63 loci and a dual-fusion probe for TBL1XR1/TP63 fusion [inv(3)(q26q28)]. Evaluation for rearrangements was performed without knowledge of the specific PTCL diagnosis, clinical course, or outcome. Results At a median FU of 10.7 years (range: 7-14 yrs), 71 of 160 (44,4%) intention-to-treat population patients were still alive and in remission. Causes of death for the 89 deceased patients were: lymphoma (76%), toxicity (10%), second malignancy (6%), other causes (8%). The 10-year OS, PFS and DSS for the whole ITTP were 41%, 38% and 51%, respectively (all CI95% within +/- 10% range). The multivariate analysis for long-term outcome-related parameters confirmed that female patients had a significantly better outcome than their male counterparts (10 yr OS: 68% vs 47%; HR 0.60 - CI95% 0.37-0.97; p=0.039). Elevated International Prognostic Index (IPI) parameters also retained their adverse prognostic impact, in particular age (pr year) (OS: HR 1.03 - CI95% 1.00-1.06; p=0.004 and PFS: HR 1.03 - CI95% 1.01-1.06; p=0.03) and poor performance score (PS ≥2) (OS: HR 1.71 - CI95% 1.08-2.72; p=0.023 and PFS: HR 1.84 - CI95% 1.18-2.86; p=0.009). DUSP22 analysis revealed presence of a classical DUSP22-IRF4 rearrangement in six patients. All of them achieved a complete remission (CR), four stayed in continuous CR for all the follow-up period, one experienced a late relapse approximately 5 years after end of 1st line treatment and responded to 2nd line treatment with a new sustained ongoing CR, and one died of sepsis after high-dose therapy while in CR. TP63 rearrangement was found in one patient, who responded to trial therapy and was in long-term CR at the time of follow-up analysis Fig.1 shows OS according to histological subtypes among the 87 patients analyzed for DUSP22 and TP63 rearrangements. Conclusions Long-term follow up of the Nordic NLG-T-01 trial, confirmed a superior outcome for female patients and an adverse prognosis for elevated IPI parameters, in particular age (per year) and PS ≥ 2. A correlative biological analysis showed a favourable outcome for ALCL patients with DUSP22/IRF4 rearrranged tumours compared to other histological subtypes, including triple negative ALCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinicopathological characteristics of PAX5 positive anaplastic large cell lymphoma with extra copies of the PAX5 gene locus

目的： 探讨PAX5阳性的间变性大细胞淋巴瘤（ALCL）的临床病理学特征。 方法： 对2例PAX5阳性的ALCL的临床特点、组织学形态、免疫表型及分子遗传学特征进行分析，并结合文献进行复习。 结果： 例1男，58岁，背部肿物，光镜下皮肤表面溃疡，真皮层见片状致密的异形的淋巴细胞浸润，肿瘤细胞中等大到大，呈免疫母细胞样，散在分布R-S样细胞；例2女，34岁，左颈部肿物，光镜下淋巴结结构完全破坏，在多种炎性细胞背景中散在分布异型的淋巴样细胞，肿瘤细胞大，胞质丰富，核不规则，部分呈马蹄形或肾形，可见花环样多核细胞。2例肿瘤细胞均弥漫性强表达CD30、CD43、CD5及CD4，中到强阳性表达PAX5，不同程度的表达CD2、CD3及CD7，不表达CD20、CD8、颗粒酶B、T细胞胞质内抗原（TIA1）及间变性淋巴瘤激酶（ALK），EB病毒编码的RNA（EBER）原位杂交均阴性。2例T细胞抗原（TCR）基因克隆性重排均阳性，Ig基因克隆性重排检测均阴性；PAX5/IgH基因融合检测阴性，但检测到PAX5基因拷贝数增加。例1采用局部放疗后获得完全缓解，随访21个月，患者无病生存。例2采用CHOEP（环磷酰胺+阿霉素+长春新碱+足叶乙甙+泼尼松）方案化疗2周期，颈部肿物较前退缩。 结论： PAX5阳性的ALCL非常罕见，可能与PAX5基因拷贝数增加有关。在形态和免疫表型上与其他淋巴瘤有重叠，易造成误诊，应综合临床信息、形态学特点、免疫表型及分子遗传学特征，才能作出正确诊断。.

Evolving strategies in T-cell lymphoma

Peripheral T-cell lymphomas (PTCL) are derived from post-thymic, mature T-cells and represent a clinically and biologically heterogeneous group of diseases. A common feature of the majority of PTCLs is a poor prognosis compared to their aggressive B-cell counterparts. Additionally, due to the rarity of the disease, the optimal therapy remains unknown. A large proportion of patients present with multiple poor risk factors as per the International Prognostic Index (IPI) and are rarely cured. The one exception is ALK positive anaplastic large cell lymphoma (ALCL), a group of diseases that has a much more favourable prognosis; however, those patients with ALCL and multiple IPI factors have a similar poor prognosis.

IL-2/IL-2R signaling and IL-2Rα-targeted therapy in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is aCD30-positive non-Hodgkin's T‑cell lymphoma. Despite the implementation of CD30 antibody-drug conjugate-targeted therapy into front-line treatment regimens, the prognosis of some subtypes of the disease remains unsatisfactory. In the relapsed/refractory setting, effective second-line treatment options are still lacking. However, it has been reported that blockade of direct downstream targets of activator protein‑1 (AP-1) transcription factors, which are highly dysregulated in ALCL, results in complete and sustained remission in late-stage relapsed/refractory anaplastic lymphoma kinase (ALK)-positive ALCL patients. Moreover, it has been identified that involvement of the BATF3/AP‑1 module promotes lymphomagenesis via oncogenic BATF3/IL-2/IL-2R signaling through hyperphosphorylation of ERK1/2, STAT1, and STAT5 in ALCL cells regardless of their ALK status. Therefore, targeting BATF3/IL-2/IL-2R signaling may represent anovel therapeutic alternative for ALCL patients.

BDP1 Expression Correlates with Clinical Outcomes in Activated B-Cell Diffuse Large B-Cell Lymphoma

The RNA polymerase III–specific TFIIIB complex is targeted by oncogenes and tumor suppressors, specifically the TFIIIB subunits BRF1, BRF2, and TBP. Currently, it is unclear if the TFIIIB subunit BDP1 is universally deregulated in human cancers. We performed a meta-analysis of patient data in the Oncomine database to analyze BDP1 alterations in human cancers. Herein, we report a possible role for BDP1 in non-Hodgkin’s lymphoma (NHL) for the first time. To the best of our knowledge, this is the first study to report a statistically significant decrease in BDP1 expression in patients with anaplastic lymphoma kinase–positive (ALK+) anaplastic large-cell lymphoma (ALCL) (p = 1.67 × 10−6) and Burkitt’s lymphoma (BL) (p = 1.54 × 10−11). Analysis of the BDP1 promoter identified putative binding sites for MYC, BCL6, E2F4, and KLF4 transcription factors, which were previously demonstrated to be deregulated in lymphomas. MYC and BDP1 expression were inversely correlated in ALK+ ALCL, suggesting a possible mechanism for the significant and specific decrease in BDP1 expression. In activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL), decreased BDP1 expression correlated with clinical outcomes, including recurrence at 1 year (p = 0.021) and 3 years (p = 0.005). Mortality at 1 (p = 0.030) and 3 (p = 0.012) years correlated with decreased BDP1 expression in ABC DLBCL. Together, these data suggest that BDP1 alterations may be of clinical significance in specific NHL subtypes and warrant further investigation.